Long somatic DNA-repeat expansion drives neurodegeneration in Huntington disease

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 20, 2024

Abstract Huntington Disease (HD) is a fatal genetic disease in which most striatal projection neurons (SPNs) degenerate. The central biological question about HD pathogenesis has been how the disease-causing DNA repeat expansion (CAG n ) huntingtin ( HTT gene leads to neurodegeneration after decades of apparent latency. Inherited alleles with longer CAG hasten onset; length this also changes over time, generating somatic mosaicism, and genes that regulate DNA-repeat stability can influence age-at-onset. To understand relationship between cell’s CAG-repeat its state, we developed single-cell method for measuring together genome-wide RNA expression. We found expands from 40-45 CAGs 100-500+ HD-vulnerable SPNs but not other cell types, these long expansions acquired at different times by individual SPNs. Surprisingly, 40 150 had no effect upon expression – 150-500+ shared profound gene-expression changes. These involved hundreds genes, escalated alongside further expansion, eroded positive then negative features neuronal identity, culminated senescence/apoptosis genes. Rates neuron loss across stages reflected rates entered biologically distorted state. Our results suggest repeats undergo quiet then, as they asynchronously cross high threshold, cause degenerate quickly asynchronously. conclude that, any moment course HD, have an innocuous (but unstable) gene, process almost all neuron’s life.

Language: Английский

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Cell-type-specific effects of age and sex on human cortical neurons

Neuron, Journal Year: 2024, Volume and Issue: 112(15), P. 2524 - 2539.e5

Published: June 5, 2024

Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes with advanced age. Using single-nucleus multi-omic DNA methylation transcriptome sequencing (snmCT-seq) in frontal cortex from young adult aged donors, we found widespread age- sex-related variation specific neuron types. The proportion inhibitory SST- VIP-expressing neurons was reduced donors. Excitatory had more profound age-related their gene expression than cells. Hundreds genes involved synaptic activity, including EGR1, were less expressed adults. Genes located subtelomeric regions increased age correlated telomere length. We further mapped cell-type-specific sex differences X-inactivation escape genes. Multi-omic epigenomes transcriptomes provide new insight into the effects on human neurons.

Language: Английский

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Long somatic DNA-repeat expansion drives neurodegeneration in Huntington’s disease

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Single-nucleus transcriptomic profiling of human orbitofrontal cortex reveals convergent effects of aging and psychiatric disease

Nature Neuroscience, Journal Year: 2024, Volume and Issue: 27(10), P. 2021 - 2032

Published: Sept. 3, 2024

Abstract Aging is a complex biological process and represents the largest risk factor for neurodegenerative disorders. The disorders also increased in individuals with psychiatric Here, we characterized age-related transcriptomic changes brain by profiling ~800,000 nuclei from orbitofrontal cortex 87 without diagnoses replicated findings an independent cohort 32 individuals. affects all cell types, LAMP5 + LHX6 interneurons, cell-type abundant primates, far most affected. Disrupted synaptic transmission emerged as convergently affected pathway aged tissue. Age-related overlapped observed Alzheimer’s disease across multiple types. We find evidence accelerated aging demonstrate converging signature of psychopathology Our shed light on cell-type-specific effects pathways underlying their convergence driven diagnosis.

Language: Английский

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Astrocyte Gi-GPCR signaling corrects compulsive-like grooming and anxiety-related behaviors in Sapap3 knockout mice

Neuron, Journal Year: 2024, Volume and Issue: 112(20), P. 3412 - 3423.e6

Published: Aug. 19, 2024

Astrocytes are morphologically complex cells that serve essential roles. They widely implicated in central nervous system (CNS) disorders, with changes astrocyte morphology and gene expression accompanying disease. In the Sapap3 knockout (KO) mouse model of compulsive anxiety-related behaviors related to obsessive-compulsive disorder (OCD), striatal astrocytes display reduced altered actin cytoskeleton Gi-G-protein-coupled receptor (Gi-GPCR) signaling proteins. Here, we show normalizing morphology, cytoskeleton, homeostatic support functions by targeting Gi-GPCR pathway using chemogenetics corrected phenotypes KO mice, including behaviors. Our data portend an astrocytic pharmacological strategy for rescuing brain disorders include compromised tissue support.

Language: Английский

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Astrocytes in aging

Neuron, Journal Year: 2025, Volume and Issue: 113(1), P. 109 - 126

Published: Jan. 1, 2025

Language: Английский

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Astrocytic-supplied cholesterol drives synaptic gene expression programs in developing neurons and downstream astrocytic transcriptional programs

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 28, 2025

Abstract Astrocytes participate in neuronal synaptic programs that are enriched for genetic associations schizophrenia and autism spectrum disorders (ASD). To better understand how these co-regulated cellular induced during early development, we studied astrocytes iPSC-derived neurons co-cultures mono-cultures at 16 time points spanning 0.5 hours to 8 days. We found upregulation of genes involved cholesterol biosynthesis preceded the activation gene astrocytic Nrxn1 . Neuronal knockdown key receptors led downregulation a robust transcriptional response astrocytes, including further This suggests astrocyte-supplied drives changes bi-directional signalling is occuring. The upregulated were deleterious variants neurodevelopmental disorders, suggesting their pathogenic effect may be, part, mediated by reduced buffering capacity astrocyte supply neurons. These findings highlight critical role astrocyte-neuron interactions psychiatric particularly relation lipid metabolism plasticity.

Language: Английский

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Mechanisms of astrocyte aging in reactivity and disease

Molecular Neurodegeneration, Journal Year: 2025, Volume and Issue: 20(1)

Published: Feb. 21, 2025

Normal aging alters brain functions and phenotypes. However, it is not well understood how astrocytes are impacted by aging, nor they contribute to neuronal dysfunction disease risk as organisms age. Here, we examine the transcriptional, cell biology, functional differences in across normal aging. Astrocytes at baseline heterogenous, responsive their environments, critical regulators of microenvironments function. With increasing age, adopt different immune-related senescence-associated states, which relate organelle loss homeostasis maintenance, both autonomously non-cell autonomously. These perturbed states increasingly associated with age-related onset neurodegeneration, suggesting that astrocyte a compelling target for future manipulation prevention disease.

Language: Английский

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Simultaneous CRISPR screening and spatial transcriptomics reveal intracellular, intercellular, and functional transcriptional circuits

Cell, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Highlights•Perturb-FISH combines spatial transcriptomics and readout of CRISPR perturbation•We recover the effects genetic perturbation on transcriptome single cells•We find specific networks related to cell neighbors in tissue•We connect time-resolved imaging phenotypes after perturbationSummaryPooled optical screens have enabled study cellular interactions, morphology, or dynamics at massive scale, but they not yet leveraged power highly plexed single-cell resolved transcriptomic readouts inform molecular pathways. Here, we present a combination with parallel detection situ amplified guide RNAs (Perturb-FISH). Perturb-FISH recovers intracellular that are consistent RNA-sequencing-based (Perturb-seq) screen lipopolysaccharide response cultured monocytes, it uncovers intercellular density-dependent regulation innate immune response. Similarly, three-dimensional xenograft models, identifies tumor-immune interactions altered by knockout. When paired functional separate autism spectrum disorder risk genes human-induced pluripotent stem (hIPSC) astrocytes, shows common calcium activity their associated dysregulated is thus general method for studying associations biology resolution.Graphical abstract

Language: Английский

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The Genomic Intersection of Oligodendrocyte Dynamics in Schizophrenia and Aging Unravels Novel Pathological Mechanisms and Therapeutic Potentials

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4452 - 4452

Published: April 18, 2024

Schizophrenia is a significant worldwide health concern, affecting over 20 million individuals and contributing to potential reduction in life expectancy by up 14.5 years. Despite its profound impact, the precise pathological mechanisms underlying schizophrenia continue remain enigmatic, with previous research yielding diverse occasionally conflicting findings. Nonetheless, one consistently observed phenomenon brain imaging studies of patients disruption white matter, bundles myelinated axons that provide connectivity rapid signalling between regions. Myelin produced specialised glial cells known as oligodendrocytes, which have been shown be disrupted post-mortem analyses patients. Oligodendrocytes are generated throughout major population oligodendrocyte progenitor (OPC), essential for matter plasticity. Notably, decline specific subpopulation OPC has identified principal factor loss aging brain, suggesting this may also schizophrenia. In review, we analysed genomic databases pinpoint intersections identify shared cognitive dysfunction.

Language: Английский

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